An effective vaccine for protection against retroviral infection or disease development should induce both humoral and cellular immune responses. To achieve this, a combination vaccine approach has been designed. The first component includes novel synthetic constructs to elicit a broadly cross-reactive humoral response capable of inducing cross-neutralizing antibodies. The second component incorporates recombinant BCG (bacille calmette-guerin) expressing SIV and HIV proteins to elicit a strong ctl response. The synthetic constructs, referred to as HECS (hypervariable epitope constructs), have been designed to represent the in vivo variability of individual epitopes in the siv envelope sequences available from the various databases, and using HEC technology to include each variation of the hypervariable and antigenic regions in the peptide mixture. The hecs have been tested in mice, rabbits and macaques, and found to elicit virus-neutralizing and broadly cross-reactive antibodies. Recombinant bcg expressing SIV gag, pol, env, and nef proteins were constructed by insertion of the respective genes into an E. coli to bcg shuttle vector. Each of these bcg recombinants, in combination and individually has been inoculated into mice, rabbits and monkeys by several routes, and their CTL activity, T-cell proliferation, and antibody responses assessed. To elicit strong humoral and CTL responses, a combination of the synthetic hec constructs and all four recombinant bcg constructs was inoculated into mice, rabbits and monkeys. CTL activity, T-cell proliferation, and antibody responses were analyzed. Very good immune responses have been demonstrated in several monkeys after administration of this combination vaccine. This is the first time CTL activity against more than one SIV protein has been elicited by immunization with live recombinant vectors expressing the individual SIV/HIV proteins.